CN103483293A - Synthesis method of lasofoxifene precursor of nafoxidine - Google Patents
Synthesis method of lasofoxifene precursor of nafoxidine Download PDFInfo
- Publication number
- CN103483293A CN103483293A CN201310372314.XA CN201310372314A CN103483293A CN 103483293 A CN103483293 A CN 103483293A CN 201310372314 A CN201310372314 A CN 201310372314A CN 103483293 A CN103483293 A CN 103483293A
- Authority
- CN
- China
- Prior art keywords
- phenyl
- lasofoxifene
- nafoxidine
- methoxyl group
- precursor
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 0 CCC(C)*C(*C(CCC1C2)c3ccccc3)C1=CC=C2OC Chemical compound CCC(C)*C(*C(CCC1C2)c3ccccc3)C1=CC=C2OC 0.000 description 2
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthesis method of the lasofoxifene precursor of nafoxidine (1). The synthesis method comprises the following steps of: reacting 6-methoxy-2-phenyl-1-tetralone (2) with perfluoro butanesulfonylfluoride to obtain 6-methoxy-2-phenyl-3,4-dialin-1-perfluorobutane sulfonate (3), and carrying out coupling reaction on the 6-methoxy-2-phenyl-3,4-dialin-1-perfluorobutane sulfonate (3) and a compound in the general formula 4 in the presence of cuprous chloride, lithium chloride, and an iron catalyst, to obtain the nafoxidine (1). The synthesis method disclosed by the invention is simple and efficient, needs mild and easily controllable reaction conditions, and is high yield, and the product is easily separated.
Description
Technical field
The invention belongs to chemosynthesis technical field, be specifically related to treat the postmenopausal women osteoporosis agents Lasofoxifene precursor nafoxidine (
1) a kind of synthetic method.
Background technology
D-lasofoxifene tartrate (lasofoxifene D-tartrate) is a kind of oestrogenic hormon partial agonist of Pfizer's exploitation, and its listing formulation is thin membrane coated tablet, and commodity are called Fablyn.It has the blocking-up bone loss, reduces the effect of cholesterol, in Europe, go on the market at present, every per daily dose only needs 0.5mg, the oestrogenic hormon partial agonist [Wang Wei that at present the most potent having blocked bone loss, reduced the effect of cholesterol, Ai Min. the new drug Lasofoxifene for the treatment of osteoporosis
the pharmacy progress,
2005, 29 (2): 2-3].Its II phase is clinical has compared the RALOXIFENE HCL (raloxifene that D-lasofoxifene tartrate and gift carry out company's exploitation, 60mg/ day) curative effect, the D-lasofoxifene tartrate increases lumbar spine bmd, with the effect that reduces low density lipoprotein cholesterol, all is better than RALOXIFENE HCL.
D-lasofoxifene tartrate (lasofoxifene D-tartrate)
Nafoxidine (
1) be a kind of non steroidal estrogen antagonist of finding the sixties in 20th century, but success as medicinal, but due to the most succinct synthetic route of D-lasofoxifene tartrate be with nafoxidine (
1) be raw material, split through over hydrogenation, demethylation, with D-tartrate salify and obtain [US005552412A and Tong Ling, Zhu Xueyan, Yuan Zhedong.
chinese Journal of Pharmaceuticals,
2011, 42 (7): 481-483], however synthetic difficult point not at rear three-step reaction, and be its precursor nafoxidine (
1) synthetic.So nafoxidine (
1) the synthetic concern that has caused again people.
Reported in literature nafoxidine (
1) many synthetic routes [Li Dan, Wang Zhefeng, Wang little Mei, Shi Huilin. the lasofoxifene tartrate synthesis scheme.
chinese Journal of Pharmaceuticals.
2010, 41 (6): 468-471], wherein comparatively succinct, representative route has two: respectively with 6-methoxyl group-2-phenyl-ALPHA-tetralone (
2) or 6-methoxyl group-ALPHA-tetralone be starting raw material.
route 1: the 6-methoxyl group-2-phenyl-ALPHA-tetralone (2) of take is starting raw material.
Early stage United States Patent (USP) (US3274213,1966) has been reported in anhydrous THF 1-(2-(4-bromine phenoxy group) ethyl) tetramethyleneimine has been made to Grignard reagent, then under the condition refluxed with 6-methoxyl group-2-phenyl-ALPHA-tetralone (
2) carry out the Ge Shi addition, obtain nafoxidine (
1), yield is only 24%(condition A).
Patent WO2012/159981 A2 has adopted identical route, but processing condition difference, under low temperature (78 ℃), use n-Butyl Lithium, 1-(2-(4-bromine phenoxy group) ethyl) tetramethyleneimine is made to organolithium reagent, and under the existence of anhydrous cerous compounds, with 6-methoxyl group-2-phenyl-ALPHA-tetralone (
2) carry out addition reaction, obtain nafoxidine (
1), yield is 28%(condition B).This reaction needed is carried out under low temperature (78 ℃), and last handling process need to use high vacuum underpressure distillation (0.2mmHg) and remove impurity, operates comparatively loaded down with trivial detailsly, and very high to the requirement of equipment, makes the with high costs of this operational path.Compare article one route, yield does not obviously improve, and there is no the advantage on cost yet, but constant product quality.
route 2: take 6-methoxyl group-ALPHA-tetralone as starting raw material.
United States Patent (USP) (US005552412A, 1996) reported and in anhydrous THF, used n-Butyl Lithium that 1-(2-(4-bromine phenoxy group) ethyl) tetramethyleneimine is made to organolithium reagent, carry out addition reaction with cheap 6-methoxyl group-ALPHA-tetralone under the existence of anhydrous cerous compounds, and remove impurity by high vacuum underpressure distillation (0.15mmHg).Re-use pyridinium tribromide and carry out bromo-reaction.Last and phenylo boric acid carries out the Suzuki coupling, obtain nafoxidine (
1), the bromination reaction by product in this route is more, and is difficult to separate, and the catalyzer cost of Suzuki linked reaction is higher and can't reclaim.This route total recovery is 37% (condition A).
Tong Ling etc. [Tong Ling, Zhu Xueyan, Yuan Zhedong.
chinese Journal of Pharmaceuticals,
2011, 42 (7): 481-483] route in patent US005552412A is optimized, make total recovery be promoted to 50%.
U.S. Pat 2012/0045648 A1 has adopted identical route, and just the processing condition difference of the first step reaction, adopt Grignard reagent to replace organolithium reagent to be reacted, but concrete temperature of reaction and separation method are not mentioned.This route total recovery is 42% (condition B).
Summary of the invention
The object of the present invention is to provide Lasofoxifene precursor nafoxidine (
1) a kind of synthetic method.
The present invention with 6-methoxyl group-2-phenyl-ALPHA-tetralone (
2) as raw material, under the existence of DBU, with perfluoro butyl sulfonic acid fluoride, react, obtain 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3), then at cuprous chloride, under the existence of lithium chloride and iron catalyst, with general formula
4compound carry out linked reaction, obtain nafoxidine (
1), reaction formula is as follows:
1) 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3) synthetic
Usually the preparation method of perfluoro butyl sulphonate is: at tetrahydrofuran (THF) or methylene dichloride, by perfluoro butyl sulfonic acid fluoride under the existence of organic bases (DBU, triethylamine, hmds lithium etc.), react and obtain with carbonyl compound, this reaction is at room temperature carried out usually.In recent years perfluoro butyl sulfonic acid fluoride by electrolysis process in industrial tons of scale operation, with low cost, and nontoxic pollution-free.[Science?Update，
E-Newsletter.?
2003.9
:?3-6?/?Michael?Alexander?Kolja?Vogel,?
Dissertation，Freie?
?Berlin，
2009,?30-33]。
In the present invention by 6-methoxyl group-2-phenyl-ALPHA-tetralone (
2) be dissolved in organic solvent, at room temperature add DBU, more slowly add perfluoro butyl sulfonic acid fluoride, stirring reaction 4-60h.Add the water washing organic phase, then add and the washing of the dilute hydrochloric acid solution of DBU equivalent, finally, with the saturated nacl aqueous solution washing, the pressure reducing and steaming solvent, obtain 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3).
Wherein, described organic solvent is tetrahydrofuran (THF) or methylene dichloride, selects the methylene dichloride effect better.Solvent load and 6-methoxyl group-2-phenyl-ALPHA-tetralone (
2) ratio be controlled at 5-15, usually reaction adopts ratio 8.
Described step 1) 6-methoxyl group-2-phenyl-ALPHA-tetralone (
2) with the molar ratio range of perfluoro butyl sulfonic acid fluoride be 1:1 ~ 5, the best is 1:1.4.
2) nafoxidine (
1) synthetic
The Grignard reagent linked reaction, be by thiazolinyl or aryl substituent under the existence of metal catalyst, carry out linked reaction with Grignard reagent; Metal catalyst is palladium, nickel.
Palladium and nickel and other heavy metal catalysts are because the reaction type of its application is more extensive, and comparatively ripe, and the parent who is subject to people looks at, but high owing to existing price, poisonous and harmful, usually need to participate in hypertoxic phosphine part, and the substrate of the linked reaction of palladium and nickel catalysis is generally comparatively unsettled bromide and iodide.Large quantity research shows in recent years, advantages such as iron catalyst not only has efficiently, low toxicity, environmental protection, and reaction substrate not only can use bromide and iodide, can also use stable and cheap muriate and sulphonate [Wang Chen, Fu Yao etc.
organic chemistry,
2007, 27:703-723], and reaction conditions does not have the heavy metal catalysts such as palladium and nickel so harsh.Therefore iron catalyst is widely applied in organic synthesis.
Reference literature method of the present invention [Michael Alexander Kolja Vogel,
dissertation. Freie
berlin,
2009: 55-64], adopt iron catalyst, developed prepare nafoxidine (
1) novel process.
To general formula
4the THF solution of compound in, add cuprous chloride and lithium chloride, then add 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3) THF solution and iron catalyst, react 0.5 ~ 5h under-30 ℃ ~ 40 ℃.Reaction solution is poured in saturated ammonium chloride, and solids removed by filtration, collect filtrate.The phase of minute anhydrating, and extracting by ethyl acetate, merge organic phase, and finally, with the saturated sodium-chloride washing, anhydrous sodium sulfate drying, filter, the pressure reducing and steaming solvent, obtain nafoxidine (
1).
Wherein, described step 2) general formula
4compound in, M is MgBr or Li.
Described step 2) general formula
4compound and 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3) molar ratio range be 1:0.5 ~ 2, the best is 1:1; Cuprous chloride and 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3) molar ratio range be 1:0.5 ~ 3, the best is 1:1; Iron catalyst and 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3) molar ratio range be 1:0.5 ~ 5, the best is 1:1; The molar ratio range of cuprous chloride and lithium chloride is 1:1 ~ 5, and the best is 1:2; The temperature of linked reaction is-30 ℃ ~ 40 ℃, and the reaction times is 0.5 ~ 5h.
Described step 2) iron catalyst is a kind of in iron(ic) chloride, iron bromide, ferric acetyl acetonade.While using ferric acetyl acetonade to do, reaction effect is best.Ferric acetyl acetonade and 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3) ratio be controlled at 0.5-2, when ratio is 1, reaction yield is the highest.
Described step 2) THF and 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3) ratio be controlled at 5-15, usually reaction adopts ratio 8.
Advantage of the present invention and innovative point are:
The invention provides a kind of succinct nafoxidine efficiently (
1) synthetic method: use nontoxic and safe perfluoro butyl sulfonic acid fluoride, cheap free of contamination iron catalyst is reacted, and the reaction conditions gentleness is easy to control, and the high and product of yield easily separates.Solved in prior art operational path loaded down with trivial details, complicated operation, by product is many, the problems such as separation difficulty.Also solved the source problem that comes of D-lasofoxifene tartrate raw material simultaneously.
The accompanying drawing explanation
Fig. 1 is 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3)
1h NMR
Fig. 2 is 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3)
13c NMR
Fig. 3 be nafoxidine (
1)
1h NMR
Embodiment
The present invention will be further described by the following examples, but the present invention is not limited only to this.
Embodiment 1:
At room temperature by 6-methoxyl group-2-phenyl-ALPHA-tetralone (
2) (15.0g, 59.5mmol) be dissolved in methylene dichloride (120mL), adds DBU(12.6g, 83.3mmol).Slowly add perfluoro butyl sulfonic acid fluoride (25.2g, 83.3mmol) in reaction solution, about 20min adds.At room temperature stir 16h.Add distilled water 120mL * 2 washings in reaction solution, and add 0.5N hydrochloric acid soln 167mL, divide the phase of anhydrating, and extract with methylene dichloride 100mL * 2, merge organic phase, saturated nacl aqueous solution 100mL washing, anhydrous sodium sulfate drying, filter, concentrated filtrate obtains 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3) 30.0g, faint yellow oily matter, productive rate 94.3%.
6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3)
1h NMR (500 MHz, CDCl
3) see Fig. 1: δ 7.51 (d,
j=8.5 Hz, 1H), 7.49 – 7.43 (m, 4H), 7.43 – 7.34 (m, 1H), 6.89 (dd,
j=8.6/2.6 Hz, 1H), 6.85 (d, J=2.4 Hz, 1H), 3.88 (s, 3H), 3.03 (t, J=7.8 Hz, 2H), 2.83 (t, J=7.9 Hz, 2H).
6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3)
13c NMR (126 MHz, CDCl
3) see Fig. 2: δ 160.13,141.27,138.00,136.46,129.64,129.20,128.44,123.68,123.07,113.86,111.48,55.28,30.35,28.27, in product, 4 of perfluoro butyl carbon exist
13in C NMR, have overlapping, [Shekhar S consistent with document description, Dunn T B, Kotecki B J, et al. A General Method for Palladium-Catalyzed Reactions of Primary Sulfonamides with Aryl Nonaflates.
j Org Chem,
2011, 76 (11): 4552 – 4563].
Embodiment 2:
At room temperature by 6-methoxyl group-2-phenyl-ALPHA-tetralone (
2) (3.00g, 11.9mmol) be dissolved in THF(25mL) in, add DBU(2.53g, 16.7mmol).Slowly add perfluoro butyl sulfonic acid fluoride (5.03g, 16.7mmol) in reaction solution, about 15min adds.At room temperature stir 16h.Pressure reducing and steaming THF, add methylene dichloride 30mL in residue, distilled water 30mL * 2 washings, and add 0.5N hydrochloric acid soln 33.3mL, divide the phase of anhydrating, and extract with methylene dichloride 10mL, merge organic phase, saturated nacl aqueous solution 30mL washing, anhydrous sodium sulfate drying, filter, concentrated filtrate obtains 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3) 5.89g, faint yellow oily matter, productive rate 92.7%.
Embodiment 3:
Under 0 ℃, toward (4-(2-(1-pyrrolidyl) oxyethyl group) phenyl-magnesium-bromide (
4) in (M=MgBr) THF solution (48mL) (11.2mmol), add CuCl(1.11g, 11.2mmol), anhydrous LiCl(0.940g, 22.5mmol), stir 1h, adding 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3) (6.00g, 11.2mmol) and ferric acetyl acetonade (3.97g, 11.2mmol), continue to stir 2h under 0 ℃.Reaction solution is poured in saturated ammonium chloride solution (50mL), and solids removed by filtration, collect filtrate.Divide the phase of anhydrating, and extract with ethyl acetate 20mL * 2, merge organic phase, the pressure reducing and steaming solvent.Add distilled water 40mL in residue, and add 2N hydrochloric acid, making pH is 2 ~ 3, adds the mixed solution 20mL of ether and methyltetrahydrofuran * 2(1:3 v/v) extract, minute go organic phase, and extract with 0.5N hydrochloric acid 30mL, merge water, add the 4N sodium hydroxide solution, making pH is 11 ~ 12, add ethyl acetate 30mL * 2 to extract, divide the phase of anhydrating.Organic phase adds saturated nacl aqueous solution 50mL washing, and organic phase, through anhydrous sodium sulfate drying, is filtered, concentrated nafoxidine (
1) 4.23g, white crystals, productive rate 88.6%.
Nafoxidine (
1)
1h NMR (500 MHz, CDCl
3) as shown in Figure 3, δ 7.13 (t,
j=7.4 Hz, 2H), 7.09 – 7.03 (m, 3H), 6.99 (d,
j=8.5 Hz, 2H), 6.80 (m, 4H), 6.63 (dd,
j=8.6,2.7 Hz, 1H), 4.10 (t,
j=6.0 Hz, 2H), 3.82 (s, 3H), 2.99 – 2.95 (m, 2H), 2.92 (t,
j=6.0 Hz, 2H), 2.81 (dd,
j=9.2,6.3 Hz, 2H), 2.66 (s, 4H), 1.87 – 1.82 (m, 4H) [consistent with patent WO2012/159981 A2]
Embodiment 4:
Under-10 ℃, toward (4-(2-(1-pyrrolidyl) oxyethyl group) phenyl-magnesium-bromide (
4) in (M=MgBr) THF solution (32mL) (7.49mmol), add CuCl(0.740g, 7.49mmol), LiCl(0.630g, 15.0mmol), stir 1h, adding 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3) (4.00g, 7.49mmol) and iron(ic) chloride (1.31g, 7.91mmol), continue to stir 3h under-10 ℃.Reaction solution is poured in saturated ammonium chloride solution (40mL), and solids removed by filtration, collect filtrate.Divide the phase of anhydrating, and extract with ethyl acetate 15mL * 2, merge organic phase, the pressure reducing and steaming solvent.Add distilled water 30mL in residue, and add 2N hydrochloric acid, making pH is 2 ~ 3, and add mixed solution 15 mL of ether and methyltetrahydrofuran * 2(1:3 v/v) extract, minute go organic phase, and extract with 0.5N hydrochloric acid 20mL, merge water, add the 4N sodium hydroxide solution, making pH is 11 ~ 12, add ethyl acetate 20mL * 2 to extract, divide the phase of anhydrating, organic phase adds L saturated nacl aqueous solution 35m washing, anhydrous sodium sulfate drying, filter, concentrated filtrate obtain nafoxidine (
1) 2.68g, white crystals, productive rate 84.2%.
Embodiment 5:
Under 25 ℃, toward (4-(2-(1-pyrrolidyl) oxyethyl group) phenyl-magnesium-bromide (
4) in (M=MgBr) THF solution (160mL) (37.5mmol), add CuCl(3.70g, 37.5mmol), LiCl(3.15g, 74.9mmol), stir 0.5h, adding 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3) (20.0g, 37.5mmol) and iron bromide (11.6g, 39.3mmol), continue to stir 0.5h under 40 ℃.Reaction solution is poured in saturated ammonium chloride solution (200mL), and solids removed by filtration, collect filtrate.Divide the phase of anhydrating, and extract with ethyl acetate 75mL * 2, merge organic phase, the pressure reducing and steaming solvent.Add distilled water 150mL in residue, and add 2N hydrochloric acid, making pH is 2 ~ 3, and add the mixed solution 75mL of ether and methyltetrahydrofuran * 2(1:3 v/v) extract, minute go organic phase, and extract with 0.5N hydrochloric acid 100mL, merge water, add the 4N sodium hydroxide solution, making pH is 11 ~ 12, add ethyl acetate 75mL * 2 to extract, divide the phase of anhydrating, organic phase adds saturated nacl aqueous solution 175mL washing, anhydrous sodium sulfate drying, filter, concentrated filtrate obtain nafoxidine (
1) 13.3g, white crystals, productive rate 83.3%.
Embodiment 6:
Under-30 ℃, toward (4-(2-(1-pyrrolidyl) oxyethyl group) phenyl lithium (
4) in (M=Li) THF solution (60mL) (14.1mmol), add CuCl(1.39g, 14.0mmol), LiCl(1.18g, 28.1mmol), stir 2h, adding 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3) (7.50g, 14.0mmol) and ferric acetyl acetonade (4.96g, 14.0mmol), continue to stir 5h under-30 ℃.Reaction solution is poured in saturated ammonium chloride solution (60mL), and solids removed by filtration, collect filtrate.Divide the phase of anhydrating, and extract with ethyl acetate 20mL * 2, merge organic phase, the pressure reducing and steaming solvent.Add distilled water 50mL in residue, and add 2N hydrochloric acid, making pH is 2 ~ 3, and add the mixed solution 25mL of ether and methyltetrahydrofuran * 2(1:3 v/v) extract, minute go organic phase, and extract with 0.5N hydrochloric acid 30mL, merge water, add the 4N sodium hydroxide solution, making pH is 11 ~ 12, add ethyl acetate 30mL * 2 to extract, divide the phase of anhydrating, organic phase adds saturated nacl aqueous solution 50mL washing, anhydrous sodium sulfate drying, filter, concentrated filtrate obtain nafoxidine (
1) 5.33g, white crystals, productive rate 89.3%.
Embodiment 7:
Under-20 ℃, toward (4-(2-(1-pyrrolidyl) oxyethyl group) phenyl lithium (
4) add CuCl(22.2g, 225mmol in (M=Li) THF solution (1L) (225mmol)), LiCl(18.9g, 450 mmol), stir 1.5h, adding 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3) (120 g, 225mmol) and iron(ic) chloride (39.0g, 236mmol), continue to stir 3h under-20 ℃.Reaction solution is poured in saturated ammonium chloride solution (1L), and solids removed by filtration, collect filtrate.Divide the phase of anhydrating, and extract with ethyl acetate 300mL * 2, merge organic phase, the pressure reducing and steaming solvent.Add distilled water 700mL in residue, and add 2N hydrochloric acid, making pH is 2 ~ 3, and add the mixed solution 250mL of ether and methyltetrahydrofuran * 2(1:3 v/v) extract, minute go organic phase, and extract with 0.5N hydrochloric acid 300mL, merge water, add the 4N sodium hydroxide solution, making pH is 11 ~ 12, add ethyl acetate 350mL * 2 to extract, divide the phase of anhydrating, organic phase adds saturated nacl aqueous solution 500mL washing, anhydrous sodium sulfate drying, filter, concentrated filtrate obtain nafoxidine (
1) 83.4g, white crystals, productive rate 87.3%.
Embodiment 8:
Under-30 ℃, the lithium reagent of 1-(2-(4-bromine phenoxy group) ethyl) tetramethyleneimine (
4) add CuCl(0.370g, 3.74mmol in (M=Li) THF solution (16mL) (3.74mmol)), LiCl(0.310g, 7.48mmol), stir 2h, adding 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3) (2.00g, 3.74mmol) and iron bromide (1.11g, 3.74mmol), continue to stir 1h under 0 ℃.Reaction solution is poured in saturated ammonium chloride solution (16mL), and solids removed by filtration, collect filtrate.Divide the phase of anhydrating, and extract with ethyl acetate 10mL * 2, merge organic phase, the pressure reducing and steaming solvent.Add distilled water 10mL in residue, and add 2N hydrochloric acid, making pH is 2 ~ 3, and add the mixed solution 10mL of ether and methyltetrahydrofuran * 2(1:3 v/v) extract, minute go organic phase, and extract with 0.5N hydrochloric acid 15mL, merge water, add the 4N sodium hydroxide solution, making pH is 11 ~ 12, add ethyl acetate 10mL * 2 to extract, divide the phase of anhydrating, organic phase adds saturated nacl aqueous solution 15mL washing, anhydrous sodium sulfate drying, filter, concentrated filtrate obtain nafoxidine (
1) 1.35g, white crystals, productive rate 84.9%.
Claims (9)
1. the synthetic method of Lasofoxifene precursor nafoxidine, is characterized in that comprising the steps:
1) 6-methoxyl group-2-phenyl-ALPHA-tetralone (
2) with perfluoro butyl sulfonic acid fluoride, react, obtain 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3);
2) 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3) under the existence of cuprous chloride, lithium chloride and iron catalyst, with general formula
4compound carry out linked reaction, obtain nafoxidine (
1).
2. the synthetic method of Lasofoxifene precursor nafoxidine according to claim 1 is characterized in that: described step 1) 6-methoxyl group-2-phenyl-ALPHA-tetralone (
2) with the molar ratio range of perfluoro butyl sulfonic acid fluoride be 1:1 ~ 5, the best is 1:1.4.
3. the synthetic method of Lasofoxifene precursor nafoxidine according to claim 1, is characterized in that: described step 2) general formula
4compound in, M is MgBr or Li.
4. the synthetic method of Lasofoxifene precursor nafoxidine according to claim 1 is characterized in that: described step 2) iron catalyst is a kind of in iron(ic) chloride, iron bromide, ferric acetyl acetonade.
5. according to the synthetic method of claim 1,3,4 described Lasofoxifene precursor nafoxidines, it is characterized in that described step 2) compound and 6-methoxyl group-2-phenyl-3 of general formula 4,4-dialin-1-perfluoro butyl sulphonate (
3) molar ratio range be 1:0.5 ~ 2, the best is 1:1.
6. according to the synthetic method of claim 1,3,4 described Lasofoxifene precursor nafoxidines, it is characterized in that described step 2) cuprous chloride and 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3) molar ratio range be 1:0.5 ~ 3, the best is 1:1.
7. according to the synthetic method of claim 1,3,4 described Lasofoxifene precursor nafoxidines, it is characterized in that described step 2) iron catalyst and 6-methoxyl group-2-phenyl-3,4-dialin-1-perfluoro butyl sulphonate (
3) molar ratio range be 1:0.5 ~ 5, the best is 1:1.
8. according to the synthetic method of claim 1,3,4 described Lasofoxifene precursor nafoxidines, it is characterized in that described step 2) molar ratio range of cuprous chloride and lithium chloride is 1:1 ~ 5, the best is 1:2.
9. according to the synthetic method of claim 1,3,4 described Lasofoxifene precursor nafoxidines, it is characterized in that described step 2) the temperature of linked reaction be-30 ℃ ~ 40 ℃, the reaction times is 0.5 ~ 5h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310372314.XA CN103483293B (en) | 2013-08-24 | 2013-08-24 | Synthesis method of lasofoxifene precursor of nafoxidine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310372314.XA CN103483293B (en) | 2013-08-24 | 2013-08-24 | Synthesis method of lasofoxifene precursor of nafoxidine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103483293A true CN103483293A (en) | 2014-01-01 |
| CN103483293B CN103483293B (en) | 2015-01-07 |
Family
ID=49823942
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310372314.XA Active CN103483293B (en) | 2013-08-24 | 2013-08-24 | Synthesis method of lasofoxifene precursor of nafoxidine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103483293B (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6608212B1 (en) * | 2002-06-04 | 2003-08-19 | Pfizer, Inc. | Process for preparing vinylaromatic compounds |
| WO2007086471A1 (en) * | 2006-01-26 | 2007-08-02 | Tokyo University Of Science Educational Foundation Administrative Organization | Process for production of lasofoxifene or analogue thereof |
| CN101300209A (en) * | 2005-09-12 | 2008-11-05 | 赛拓有限责任公司 | Nickel or iron catalysed carbon-carbon coupling reaction of arylenes, alkenes and alkines |
| WO2012159981A2 (en) * | 2011-05-20 | 2012-11-29 | Lek Pharmaceuticals D.D. | PROCESS FOR THE PREPARATION OF α-SUBSTITUTED KETONES AND THEIR APPLICATION IN SYNTHESIS OF PHARMACEUTICALLY ACTIVE COMPOUNDS |
| CN103113323A (en) * | 2013-02-05 | 2013-05-22 | 南京华威医药科技开发有限公司 | Preparation method of lasofoxifene tartrate intermediate compound |
-
2013
- 2013-08-24 CN CN201310372314.XA patent/CN103483293B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6608212B1 (en) * | 2002-06-04 | 2003-08-19 | Pfizer, Inc. | Process for preparing vinylaromatic compounds |
| CN101300209A (en) * | 2005-09-12 | 2008-11-05 | 赛拓有限责任公司 | Nickel or iron catalysed carbon-carbon coupling reaction of arylenes, alkenes and alkines |
| WO2007086471A1 (en) * | 2006-01-26 | 2007-08-02 | Tokyo University Of Science Educational Foundation Administrative Organization | Process for production of lasofoxifene or analogue thereof |
| WO2012159981A2 (en) * | 2011-05-20 | 2012-11-29 | Lek Pharmaceuticals D.D. | PROCESS FOR THE PREPARATION OF α-SUBSTITUTED KETONES AND THEIR APPLICATION IN SYNTHESIS OF PHARMACEUTICALLY ACTIVE COMPOUNDS |
| CN103113323A (en) * | 2013-02-05 | 2013-05-22 | 南京华威医药科技开发有限公司 | Preparation method of lasofoxifene tartrate intermediate compound |
Non-Patent Citations (5)
| Title |
|---|
| BENJAMIN D.SHERRY ET AL.: "The Promise and Challenge of Iron-Catalyzed Cross Coupling", 《ACC.CHEM.RES》 * |
| KENYA NAKATA ET AL.: "Synthesis of Lasofoxifene, Nafoxidine and Their Positional Isomers via the Novel Three-Component Coupling Reaction", 《MOLECULES》 * |
| 张亮等: "金属催化下芳基磺酸酯偶联反应的研究进展", 《有机化学》 * |
| 童玲等: "酒石酸拉索昔芬的合成", 《中国医药工业杂志》 * |
| 黄炳南: "全氟磺酸酯在合成上的新应用", 《有机化学》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103483293B (en) | 2015-01-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103087105B (en) | Chiral phosphine ligand and comprise the metal catalyst of this part and their application | |
| EP2235023B1 (en) | An efficient process to induce enantioselectivity in procarbonyl compounds | |
| CN105408302B (en) | The method for preparing the amines of purified form | |
| CN106146459A (en) | A kind of preparation method of bilastine | |
| CN104844399B (en) | A kind of method synthesizing 2-fluorophenol compound | |
| JP2004051592A (en) | Method for producing 5-(2'-pyridyl)-2-pyridone derivative | |
| CN105949118A (en) | Preparation method of 2-aryl quinoline derivatives | |
| CN103694153B (en) | The method of styracin and arylsulfinate Reactive Synthesis alkenyl sulfone compound | |
| CN103483293B (en) | Synthesis method of lasofoxifene precursor of nafoxidine | |
| CN107056590A (en) | One kind prepares and purifies the commercial run of 4,4 ' dimethoxytrityl chloromethanes | |
| CN109096119B (en) | A method of preparing cinacalcet hydrochloride | |
| CN106831863B (en) | Montelukast sodium intermediate and its preparation method and application | |
| JP6096465B2 (en) | Method for preparing 2-alkoxy-5- (pyridin-2-yl) pyridine, an intermediate of peranpanel | |
| CN102584512B (en) | Method for synthesizing benzofuran derivatives in one pot process | |
| CN106278914B (en) | A kind of synthesis technique of increase production of amines | |
| CN110803985B (en) | Preparation method of bilastine intermediate | |
| CN106588779A (en) | Method for synthesizing dexmedetomidine hydrochloride intermediate | |
| CN107365301B (en) | Synthesis method of crizotinib and preparation method of intermediate thereof | |
| CN111116493B (en) | Method for preparing Apabetalone, intermediate and preparation method of intermediate | |
| CN104230723B (en) | The synthetic method of toremifene | |
| CN102786427A (en) | Synthetic method of bis-(2-dimethylaminoethyl)ether | |
| CN104860975B (en) | A kind of preparation method of bortezomib synthetic intermediate | |
| CN105348197A (en) | Preparation method of lorcaserin hydrochloride | |
| CN106946771B (en) | A kind of preparation method of 3- pyridone class compound | |
| CN110590619B (en) | Synthetic method of diaryl sulfone compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20201211 Address after: No.279, Zhongxia, Gushan Town, Jin'an District, Fuzhou City, Fujian Province Patentee after: FUZHOU NEPTUNUS FUYAO PHARMACEUTICAL Co.,Ltd. Address before: 350007 No. 25, progressive Road, Cangshan District, Fujian, Fuzhou Patentee before: FUJIAN INSTITUTE OF MICROBIOLOGY |
|
| TR01 | Transfer of patent right |